Diabetes mellitus (“diabetes”) is a medical disorder characterized by persistent variable hyperglycemia (i.e. high blood sugar levels). It can result from either inadequate secretion of the hormone insulin, an inadequate response by the body to insulin, or a combination of these factors. The most common forms of diabetes are type 1, type 2 and gestational diabetes.
Type 1 diabetes (T1D, also known as “childhood”, “juvenile” or “insulin-dependent” diabetes) is most commonly diagnosed in children and adolescents. It is an autoimmune disorder, in which the patient's own immune system attacks the beta cells in the Islets of Langerhans of the pancreas—where insulin is produced, and/or the insulin molecule itself. Consequently, patients with clinical T1D require regular insulin replacement therapy, immunosuppression treatment or even more experimental therapies such as islet transplantation and stem cell therapy. However, none of these treatments are ideal. While insulin replacement therapy and immunosuppression require long term treatment and cannot eradicate all diabetes induced complications, islet transplantation and stem cell therapy are not widely available and are very expensive.
Throughout the world the percentage incidence of T1D is increasing, and this is especially true of the early onset form of T1D, which affects children under the age of 4 yrs. Currently in North America T1D affects approximately 1 in 300 people and accounts for approximately 10% of all diabetic cases.
T1D is a multigenetic disorder, with up to 20 genes known to contribute. Of these, the major genetic susceptibility determinants are the human leukocyte antigen (HLA) class II alleles, HLA-DR and HLA-DQ, which are associated with up to 50% of all T1D cases. However, genetic factors alone cannot account for a person's susceptibility to the disease. For instance, less than 10% of new T1D patients have an affected family member, while the concordance between genetically identical twins is only approximately 50%. In addition, the incidence of T1D is rising far too rapidly to be attributed merely to the inheritance of diabetogenic genes. Thus, it is widely acknowledged that non-genetic, environmental factors (e.g. nutrition, infectious agents) must also play an important role in either the triggering or progression of the disease process, or both.
Indeed, several prospective studies have suggested that factors operating early in life may play an important role in the etiopathogenesis of T1D (Akerblom H. K. Vaarala O, Hyoty H, Ilonen J, Knip M., Environmental factors in the etiology of type 1 diabetes, 2002, Am. J. Med. Genet. May, 115(1), 18-29). Amongst the environmental factors that may be involved, dietary factors operating early in life, i.e. short breast feeding, early exposure to cow's milk, early introduction of gluten, have been suggested to increase the risk of developing the disease (Virtanen S. M. & Knip M. Nutritional risk predictors of beta cell autoimmunity and type 1 diabetes at a young age, 2003, Am. J. Clin. Nutr., December, 78(6), 1053-1067; and Ziegler A. G. Schmid S, Huber D, Hummel M, Bonifacio E., Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies, 2003, J. Am. Med. Assoc, October, 290(13), 1721-1728).
The non-genetic factors that contribute to T1D susceptibility are even less well defined than the genetic factors. In particular, there is little verifiable evidence of the specific contribution of non-genetic factors to T1D or how such factors interact with and influence the known genetic predeterminants.
The clinical onset (i.e. the insulin-dependent stage) of T1D is preceded by a sub-clinical phase, that can last up to several years, during which the insulin-producing islet cells and/or the patient's insulin are progressively destroyed. The sub-clinical phase is typically characterized by the presence of autoantibodies, which target one or more of the subject's islet cells (islet cell antibodies, ICAs), insulin (insulin autoantibodies, IAAs), glutamic acid decarboxylase (glutamic acid decarboxylase autoantibodies, GADAs) and tyrosine phosphatase (tyrosine phosphatase autoantibodies, IA-2As). Accordingly, there is potentially a window of opportunity during which subjects at risk of T1D may be identified for preventative therapy.
Increasingly, combinations of markers are being used to better define the risk of diabetes. However, while the detection of two or more types of autoantibody (ICA, IAA, GADA and IA-2A) has been linked to the future onset of diabetes, significant problems remain in the selection and identification of subjects having a high probability of developing T1D, and especially of children vulnerable to the early-onset form.
In this regard, until now, the selection of candidates for T1D predictive testing has largely focused on those subjects who have a family member already with the disease. However, with a less than 10% familial correlation, this approach is entirely inadequate to provide an effective means of identifying 90% of eventual T1D patients for intervention therapy. Hence, there is a need for a reliable, effective and simple method for predicting susceptibility or predisposition to T1D, that can be readily used for large-scale screening of the general population, rather than of specific genetic sub-groups.
Although children who develop early-onset T1D (i.e. in the period 0-4 yrs) may show signs of IAAs even from birth, it is not possible to distinguish neonatal autoantibodies from transplacental maternal IgGs in the first year of life. Accordingly, of those neonatal children tested and found positive for particular autoantigens, the vast majority may not ultimately develop T1D.